Advanced CRC: Liquid Biopsies and the CRICKET Study

Wells A. Messersmith, MD, FACP: The CRICKET study addresses the issue of whether or not we can rechallenge patients who have previously gotten worse on a therapy. In other words, if you tried an approach in the first- or second-line setting, the patient got worse, and they received some other drug, can you go back to that first drug? What is the role of biomarker testing—in this case, circulating tumor DNA? We know that RAS mutations are a marker of resistance for an EGFR-targeting monoclonal antibody, and we can’t biopsy every single tumor in a patient. By taking a blood test, we’re trying to get an idea of the total burden of disease throughout that patient and learn whether or not there are clones of cells that have a resistance mutation—in this case, a RAS mutation.

This is a very small study. It has fewer than 30 patients. The responders are 4 to 6 patients, depending on whether they are confirmed or unconfirmed. This is a hypothesis-generating trial, but nonetheless, it indicated that patients who did not have detectable resistance mutations seemed to get benefit from a rechallenge. Basically, the biomarker studies confirmed what we would have hypothesized, which is that if you don’t see a resistance mutation, you would be more likely to get benefit from rechallenging. On the other hand, if the resistance mutation exists within your total tumor burden, you’re less likely to get a benefit.

In colorectal cancer, some of the most promising studies that I’ve seen in the last few years have to do with biomarkers in both screening and adjuvant therapy regimens. The most interesting data I’ve seen for quite some time are in using circulating tumor DNA to see who actually needs adjuvant therapy and who doesn’t; using circulating tumor DNA to pick up biomarkers that could be potentially actionable and using it as a screening test—as a cheap, noninvasive screening test—for all sorts of DNA mutations that could indicate several different cancers, not just colorectal cancer, but also lung, pancreas, or breast cancer. These are all initial studies.

It’s not ready for prime time, but it’s quite possible that in the next decade, instead of having an expensive, invasive colonoscopy that costs thousands of dollars and that many Americans don’t like getting, we could just have a blood test that looks for mutated pieces of DNA that shouldn’t be there in normal blood. If the test is positive, those are the patients who could then be referred for more invasive testing; presumably, just a small subset. It would be cost saving, and it would spare discomfort or any other issues with the more invasive, expensive screening tests.

Similarly, for patients who have had an operation where you know that circulating mutated DNA could be in their body, following the operation, if the circulating tumor DNA has been cleared and it’s not evident, those patients might not need postoperative therapy. Alternatively, if you are still detecting abnormal pieces of DNA in their bloodstream, those patients might be ones for whom you have to use very intensive therapy. I think that would be incredibly promising, to pick up these cases earlier. We all know that colorectal cancer is occurring in people in their 30s and in their 40s, which is why the American Cancer Society recently changed their guidelines. Instead of waiting till age 50 for average risk, they’re saying we should start getting colonoscopies at age 45. It’s reacting to this younger patient population. But wouldn’t it be better if we could just do a blood test instead of these more invasive and expensive tests to try to detect who needs to have more extensive screening and just leave the other people alone? They don’t have to have additional testing. I look forward to that day, where it can really help cut down on the incidence of colorectal cancer and help guide us on who needs to be treated after surgery.

Transcript Edited for Clarity

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Transcript:

Wells A. Messersmith, MD, FACP: The CRICKET study addresses the issue of whether or not we can rechallenge patients who have previously gotten worse on a therapy. In other words, if you tried an approach in the first- or second-line setting, the patient got worse, and they received some other drug, can you go back to that first drug? What is the role of biomarker testing—in this case, circulating tumor DNA? We know that RAS mutations are a marker of resistance for an EGFR-targeting monoclonal antibody, and we can’t biopsy every single tumor in a patient. By taking a blood test, we’re trying to get an idea of the total burden of disease throughout that patient and learn whether or not there are clones of cells that have a resistance mutation—in this case, a RAS mutation.

This is a very small study. It has fewer than 30 patients. The responders are 4 to 6 patients, depending on whether they are confirmed or unconfirmed. This is a hypothesis-generating trial, but nonetheless, it indicated that patients who did not have detectable resistance mutations seemed to get benefit from a rechallenge. Basically, the biomarker studies confirmed what we would have hypothesized, which is that if you don’t see a resistance mutation, you would be more likely to get benefit from rechallenging. On the other hand, if the resistance mutation exists within your total tumor burden, you’re less likely to get a benefit.

In colorectal cancer, some of the most promising studies that I’ve seen in the last few years have to do with biomarkers in both screening and adjuvant therapy regimens. The most interesting data I’ve seen for quite some time are in using circulating tumor DNA to see who actually needs adjuvant therapy and who doesn’t; using circulating tumor DNA to pick up biomarkers that could be potentially actionable and using it as a screening test—as a cheap, noninvasive screening test—for all sorts of DNA mutations that could indicate several different cancers, not just colorectal cancer, but also lung, pancreas, or breast cancer. These are all initial studies.

It’s not ready for prime time, but it’s quite possible that in the next decade, instead of having an expensive, invasive colonoscopy that costs thousands of dollars and that many Americans don’t like getting, we could just have a blood test that looks for mutated pieces of DNA that shouldn’t be there in normal blood. If the test is positive, those are the patients who could then be referred for more invasive testing; presumably, just a small subset. It would be cost saving, and it would spare discomfort or any other issues with the more invasive, expensive screening tests.

Similarly, for patients who have had an operation where you know that circulating mutated DNA could be in their body, following the operation, if the circulating tumor DNA has been cleared and it’s not evident, those patients might not need postoperative therapy. Alternatively, if you are still detecting abnormal pieces of DNA in their bloodstream, those patients might be ones for whom you have to use very intensive therapy. I think that would be incredibly promising, to pick up these cases earlier. We all know that colorectal cancer is occurring in people in their 30s and in their 40s, which is why the American Cancer Society recently changed their guidelines. Instead of waiting till age 50 for average risk, they’re saying we should start getting colonoscopies at age 45. It’s reacting to this younger patient population. But wouldn’t it be better if we could just do a blood test instead of these more invasive and expensive tests to try to detect who needs to have more extensive screening and just leave the other people alone? They don’t have to have additional testing. I look forward to that day, where it can really help cut down on the incidence of colorectal cancer and help guide us on who needs to be treated after surgery.